AB0525 SUSTAINED RESPONSES TO ANTI-CD38 TREATMENT WITH DARATUMUMAB IN A PATIENT WITH REFRACTORY SYSTEMIC LUPUS ERYTHEMATOSUS
Authors: T. Alexander, L. Ostendorf, R. Biesen, A. Radbruch, G. R. Burmester, F. Hiepe
Journal: Annals of the Rheumatic Diseases (2023)

<h3>Background</h3> Given their contribution to the chronicity of autoimmune response, long-lived plasma cells (PCs) resemble an attractive treatment target in systemic lupus erythematosus (SLE) and other autoantibody-mediated diseases. We have recently reported the successful treatment of daratumumab, a CD38-targeting human monoclonal antibody, in two refractory patients with SLE [1], demonstrating a clinically relevant depletion of long-lived plasma cells with marked reduction of anti-double-stranded DNA (dsDNA) antibodies and marked clinical improvement in both cases over a follow-up period of 12 months. <h3>Objectives</h3> Here, we describe the long-term clinical and serologic responses of daratumumab treatment in one patient with SLE with a follow-up of 36 months. <h3>Methods</h3> A 51-year-old woman, who suffered from active lupus nephritis WHO class-III/V with nephrotic syndrome, pericarditis, arthritis and skin rash despite treatment with mycophenolate mofetil (MMF), cyclosporine A (CsA), hydroxychloroquine (HCQ) and glucocorticoids (GC), had received 4 weekly intravenous doses of 16mg/kg daratumumab as add on to background medication, which was complemented by subcutaneous 200mg belimumab weekly, starting 4 months after the initiation of daratumumab. Autoantibodies were investigated with ELISA and type-I interferon (IFN-I) activity investigated by measuring SIGLEC-I expression on monocytes with flow cytometry. <h3>Results</h3> During follow-up, the patients´ Urinary Protein/Creatinine Ratio (UPCR) declined from 1197 mg/g at 12 months to 467mg/g Creatinine at the last follow-up, while serum creatinine remained within normal levels (Figure 1A). No flares or novel disease manifestations occurred during the 3-year observation period, although the dosage of MMF was tapered to 1g daily at 21 months and prednisolone discontinued at 33 months, respectively, after the first daratumumab administration. Serologically, serum anti-dsDNA antibodies further decreased from 254 IE/ml at the 12 months follow-up to 38 IE/ml at 36 months (Figure 1B), and complement levels for C3 were consistently within the normal range (Figure 1C). Serum IgG levels remained stable after previous substitution with two doses of 30g intravenous immunoglobulins (Figure 1D). In addition, her initially increased type-I interferon activity, determined by the flow cytometric assessment of SIGLEC-1 on freshly isolated monocytes, completely normalized during follow-up, an effect most strongly observed during the first weeks following daratumumab that further substantiated under belimumab therapy (Figure 1E). At the last follow-up, she was in complete clinical remission, with a SLEDAI-2K of 2 due to slightly elevated dsDNA antibodies (Figure 1F). No severe adverse events occurred during follow-up, and no hospitalization was required for the management of SLE, infections or comorbidities. <h3>Conclusion</h3> Our data demonstrate that the administration of daratumumab as induction therapy for refractory and serologically active SLE may provide sustained clinical responses, when combined with immunosuppression and/or belimumab as maintenance therapy to prevent recurrence of autoreactive PCs. Apparently, depletion of long-lived PCs resulted in a therapeutically relevant reduction of autoantibodies and IFN-I activity, indicating a profound disease modification with resetting the chronic autoreactive immune system into an earlier stage of development, regaining responsiveness to standard therapies. These data suggest further studies to investigate the safety and efficacy of daratumumab in SLE and other autoantibody-mediated autoimmune diseases. <h3>Reference</h3> [1]Ostendorf L, Burns M, Durek P, Heinz GA, Heinrich F, Garantziotis P, Enghard P, Richter U, Biesen R, Schneider U, Knebel F, Burmester G, Radbruch A, Mei HE, Mashreghi MF, Hiepe F, Alexander T. Targeting CD38 with Daratumumab in Refractory Systemic Lupus Erythematosus. N Engl J Med. 2020 Sep 17;383(12):1149-1155. <h3>Acknowledgements:</h3> NIL. <h3>Disclosure of Interests</h3> Tobias Alexander Grant/research support from: Janssen, Lennard Ostendorf: None declared, Robert Biesen: None declared, Andreas Radbruch: None declared, Gerd Rüdiger Burmester: None declared, Falk Hiepe: None declared.